Physostigmine salicylate is an anticholinesterase agent.
Reversal of Anticholinergic Effects
The manufacturers state that physostigmine salicylate is used to reverse the CNS effects, toxic or otherwise, resulting from clinical or toxic dosages of drugs capable of producing the anticholinergic syndrome.148, 149 Such drugs include some antihistamines (e.g., carbinoxamine), antimuscarinics (e.g., atropine, belladonna alkaloids, clidinium, cyclobenzaprine, homatropine, hyoscyamine, propantheline, scopolamine), antiparkinsonian agents (e.g., benztropine, biperiden), phenothiazines and other antipsychotic agents, and tricyclic and tetracyclic antidepressants (e.g., amitriptyline, amoxapine, desipramine, doxepin, imipramine, maprotiline, nortriptyline, protriptyline, trimipramine).148, 149 Physostigmine salicylate also has been used to reverse the anticholinergic effects that may result from intoxication with certain plants (e.g., Atropa belladonna [deadly nightshade], Brugmansia species [angels' trumpet], Datura stramonium [jimsonweed, thorn apple, locoweed], Lantana camara ).139, 148, 149
Although physostigmine salicylate may relieve the confusion, agitation, delirium, hallucinations, stupor, ataxia, and other symptoms produced by overdosage of drugs or plants with anticholinergic effects, the drug may produce severe adverse effects (e.g., asystole, seizures).148, 149, 150, 151, 152 Therefore, routine use of the drug as an antidote for overdosage of anticholinergic drugs is controversial. The American Psychiatric Association (APA) states that, unless contraindicated, use of physostigmine can be considered for severe cases of delirium induced by anticholinergics.140 APA also states that physostigmine can be considered for anticholinergic delirium associated with phenothiazines and other antipsychotic agents.146 However, the drug should be used only with close clinical monitoring.146 (See Cautions: Precautions and Contraindications.) Many clinicians believe that the drug should be used only in the treatment of severe or life-threatening symptoms of anticholinergic toxicity (e.g., extensive delirium or agitation, hallucinations, hyperthermia, severe sinus or supraventricular tachycardia, seizures) in patients who fail to respond to alternative therapy.139, 141, 142, 143, 144
Although physostigmine has been used successfully in the treatment of tricyclic antidepressant-induced anticholinergic toxicity,109, 147, 151, 152, 153, 154, 155, 156, 157, 159, 160 the drug currently is rarely used in tricyclic intoxication because of its potential to cause serious adverse effects, including seizures, bronchospasm, and bradyarrhythmias (including asystole).109, 147, 150, 151, 152, 153, 156, 157, 159 The precise role of physostigmine in the management of tricyclic overdosage remains controversial; most clinicians advise against the routine use of physostigmine in such cases,109, 147, 152, 153, 154, 155, 156, 157, 159, 161 and some clinicians recommend that the drug be reserved only for life-threatening anticholinergic symptoms refractory to other forms of treatment.109, 153, 157 For additional information on the use of physostigmine in the management of tricyclic antidepressant overdosage, see Acute Toxicity in the Tricyclic Antidepressants General Statement 28:16.04.28.
Anticholinergically induced delirium, hallucinations, coma, and cardiac arrhythmias (e.g., supraventricular tachycardia) often respond to physostigmine; however, the drug is not helpful for cardiac conduction defects or ventricular tachyarrhythmias caused by non-anticholinergically induced cardiotoxicity.
Physostigmine salicylate should not be used routinely for overdosage of these classes of drugs or plants because of its potential adverse effects, but it may be useful as adjunctive treatment if severe anticholinergic toxicity is present. For additional information on the use of physostigmine in the management of anticholinergic toxicity, see Acute Toxicity in the Antimuscarinics/Antispasmodics General Statement 12:08.08.
Physostigmine salicylate also is a useful antidote to the delirium or prolonged somnolence produced in some patients by atropine and/or scopolamine preanesthetic medications.
Physostigmine therapy, alone or combined with lecithin, has been used with variable results in a limited number of patients with dementia of the Alzheimer's type (Alzheimer's disease).117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131 In some patients, the drug has improved cognitive and/or behavioral function, while in others, there was little, if any, measurable benefit.117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131 In one study, improvement in cognitive and behavioral function was apparent in about 30% of patients treated with physostigmine.119, 120 In another study, the drug improved short-term (immediate, primary) memory but had little effect on long-term (secondary) memory.130 Additional study is necessary to determine the role, if any, of physostigmine and other cholinergic therapy in the treatment of Alzheimer's disease and to more clearly identify those patients most likely to respond.118, 119, 120, 121, 122, 123, 124, 125, 126, 130
Physostigmine salicylate has been used orally in a limited number of patients for the management of Friedreich's ataxia and other hereditary ataxias (spinocerebellar degenerations),135, 136, 137, 138 and has been designated an orphan drug by the US Food and Drug Administration (FDA) for use in these ataxias.135 Results of clinical studies to date suggest that physostigmine may improve neurologic and visual performance and produce subjective improvement in clinical manifestations of these ataxias.136, 137, 138 Although the precise mechanism of action in these ataxias is not known, it has been suggested that physostigmine may at least partially reverse a central cholinergically mediated abnormality in vestibulo-ocular function in these ataxic patients.136, 137, 138 Additional study of physostigmine for the management of hereditary ataxias is under way.137
CNS depression associated with benzodiazepines (e.g., diazepam, lorazepam) has also been reversed by physostigmine salicylate. Physostigmine has been reported to rapidly reverse the sedative and hypnotic effects of benzodiazepines and has been used postoperatively,103, 104, 105, 106, 115, 116 but the drug has had little effect on benzodiazepine-induced CNS depression in some patients106, 107, 108, 109, 110 and may induce dose-related nausea and/or vomiting;104, 108 some clinicians state that postoperative use of physostigmine be considered only in patients with substantial benzodiazepine-induced oversedation.110 There is conflicting information on the effect of physostigmine in the management of benzodiazepine overdosage109, 110, 111, 112, 113, 114 and insufficient experience to date to recommend this use.109
Physostigmine salicylate has also been used as a stimulant to peristalsis in patients with postoperative intestinal atony.
Physostigmine salicylate is usually administered by slow IV injection or by IM injection; however, the drug has also been administered subcutaneously. When administered IV, the drug should be given at a slow, controlled rate not to exceed 1 mg/minute in adults and 0.5 mg/minute in children. (See Cautions: Precautions and Contraindications). The drug has also been administered orally, but an oral dosage form is not currently commercially available.
Atropine sulfate injection should always be readily available when physostigmine is administered. 149
The usual initial adult dose of physostigmine salicylate is 0.5-2 mg. When there is no response to the initial dose, it may be repeated every 20 minutes until response occurs or adverse cholinergic effects occur. If initial doses of the drug are effective in adults, additional doses of 1-4 mg may be given as necessary at intervals (usually 30-60 minutes) as life-threatening signs (e.g., arrhythmias, seizures, deep coma) recur.
In children, use of physostigmine should be reserved for life-threatening situations only. The initial pediatric IV or IM dose of physostigmine salicylate recommended by the manufacturers is 0.02 mg/kg. Additional doses may be repeated at 5- to 10-minute intervals until response occurs, adverse cholinergic effects develop, or a total dose of 2 mg has been administered. Alternatively, children may receive doses of 0.03 mg/kg or 0.9 mg/m2 as necessary.
To reverse the anticholinergic effects of atropine sulfate or scopolamine hydrobromide injections given as preanesthetic medications, physostigmine salicylate has been given IM or IV in a dose twice that of the anticholinergic drug, on a weight basis.
Additional study on the safety and efficacy of the drug is necessary (see Uses: Alzheimer's Disease), 118, 119, 120, 121, 122, 123, 124, 125, 126, 130, 133, 134 but an oral physostigmine salicylate dosage of 2-2.5 mg every 2 hours 6 or 7 times daily has been used in the management of dementia of the Alzheimer's type (Alzheimer's disease).118, 119, 120, 121, 130 Lower oral dosages may provide minimal benefit,119, 121, 129, 130 while higher oral dosages may produce intolerable adverse effects (e.g., nausea, vomiting, excessive sweating).121, 130 Oral dosage usually has been initiated at 0.5 mg every 2 hours 6 or 7 times daily until beneficial effect was achieved, intolerable adverse effects occurred,119, 120, 121, 130 or a maximum total daily dose of 16 mg was achieved.121
When physostigmine salicylate was used to stimulate peristalsis in patients with postoperative intestinal atony, the usual adult dose was 0.5-2 mg given IV or IM.
Adverse effects of parenterally administered physostigmine salicylate are chiefly those of exaggerated response to parasympathetic stimulation and include nausea, vomiting, epigastric pain, miosis, salivation, sweating, lacrimation, dyspnea, and bronchospasm. Stimulation of the CNS, restlessness, irregular pulse, palpitation, hallucinations, muscular twitching, and weakness may also occur. Seizures, collapse, and death from respiratory paralysis and/or pulmonary edema have occurred rarely. Rapid IV administration of physostigmine may produce bradycardia, hypersalivation leading to respiratory problems, and/or seizures.148, 149 Asystole also has been reported.150, 151 Unifocal ventricular premature contractions with runs of bigeminy occurred in an 85-year-old patient with Alzheimer's disease 30 minutes after IV injection of a 1-mg dose of the drug over 1-2 minutes.133 Episodes of hypertension have also been associated with oral administration of physostigmine in a geriatric patient with Alzheimer's disease.134 Overdosage of physostigmine can cause cholinergic crisis. (See Acute Toxicity: Manifestations.)
Precautions and Contraindications
Because of the possibility of increased sensitivity to physostigmine in some patients, atropine sulfate injection should always be readily available as an antagonist and antidote for most of the effects of physostigmine. If excessive symptoms of salivation, vomiting, urination, or defecation occur with physostigmine therapy, the drug should be discontinued. If excessive sweating or nausea occurs, dosage of physostigmine should be reduced. Some clinicians recommend that patients receiving physostigmine be observed for evidence of bronchial constriction and cardiac and close clinical monitoring should always accompany use of the drug.141, 142, 144
The commercially available formulation of physostigmine salicylate injection contains sodium bisulfite, a sulfite that can cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals. The overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.
Physostigmine should be used with caution in patients with epilepsy, parkinsonian syndrome, or bradycardia. The drug should not be administered to patients with asthma, gangrene, diabetes, cardiovascular disease, mechanical obstruction of the intestinal or urogenital tract or any vagotonic state, or in patients receiving choline esters (e.g., methacholine, bethanechol) or depolarizing neuromuscular blocking agents (e.g., decamethonium, succinylcholine).
Little information is available regarding the effects of cholinesterase inhibitors, including physostigmine, on the fetus because of the rarity of maternal conditions requiring use of these drugs during pregnancy. Because physostigmine crosses the blood-brain barrier, it would be expected to cross the placenta. Transient muscular weakness has occurred in 10-20% of neonates whose mothers received anticholinesterases for the treatment of myasthenia gravis. Use of physostigmine in pregnant women requires that the potential benefit be weighed against the possible hazard to mother and fetus.
Physostigmine overdosage may induce cholinergic crisis which is characterized by excessive salivation and sweating, miosis, nausea, vomiting, diarrhea, bradycardia or tachycardia, hypotension or hypertension, confusion, seizures, coma, severe muscle weakness, and paralysis. Death may result from respiratory paralysis and/or pulmonary edema.
The most important measure in the treatment of physostigmine overdosage is mechanical ventilation with repeated bronchial aspiration. Atropine sulfate should be given IV until control of the muscarinic effects is achieved or until signs of atropine overdosage appear. Atropine sulfate doses of 2-4 mg have been given every 3-10 minutes; for children, 1-mg doses have been used. It should be considered that the skeletal muscle effects and, consequently, respiratory paralysis which can occur following physostigmine administration, are not alleviated by atropine. IV administration of pralidoxime chloride may be useful in counteracting the ganglionic and skeletal muscle effects of physostigmine. (See Pralidoxime Chloride 91:04.20.)
Physostigmine and its salts are reversible anticholinesterase agents. The drug inhibits the destructive action of acetylcholinesterase on acetylcholine and thereby prolongs and exaggerates the central and peripheral effects of acetylcholine. Thus, systemic administration of physostigmine salicylate produces generalized cholinergic responses including miosis, increased tonus of intestinal musculature, constriction of bronchi, and stimulation of secretion by salivary and sweat glands.
Physostigmine also exerts some effects not related to acetylcholinesterase inhibition. At sufficiently high dosage, it has a direct blocking action at autonomic ganglia. Although low doses of physostigmine produce no noticeable effects at the skeletal myoneural junction, high doses can cause muscle fasciculation and, ultimately, a depolarization block. Tremor, ataxia, and hallucinations may occur. Extremely high doses produce CNS depression including sleep and finally death from respiratory paralysis. Some clinical findings suggest that physostigmine can produce a transient decrease in manic symptoms as well as precipitate mental depression. There is some evidence that the drug may potentiate the cholinergic mechanisms involved in memory storage and may improve short-term memory.
Physostigmine salicylate is readily absorbed from the GI tract, mucous membranes, and subcutaneous tissue. When the drug is administered parenterally, it has an onset of action of 3-8 minutes and a duration of action of 30 minutes to 5 hours.
Absorption of physostigmine salicylate following oral administration shows considerable interindividual variation.100, 101, 102 In one study in several healthy individuals who received 2 or 3 mg of physostigmine salicylate orally as an aqueous solution, 5-12% of the dose reached systemic circulation unchanged.100 Peak blood or plasma concentrations of the drug occur within 20-50 minutes following oral administration as a solution or tablet in healthy individuals.100, 101, 102 Following oral administration of a single 2-mg dose of physostigmine salicylate in several healthy individuals, peak blood or plasma concentrations were 0.45-2.3 ng/mL.100, 102 There is some evidence that orally administered physostigmine may undergo saturable metabolism prior to systemic circulation.100, 101, 102, 103 Individual differences in metabolic clearance of the drug may contribute to the variable absorption.100, 101, 102, 103
Physostigmine is widely distributed throughout the body. In contrast to neostigmine and pyridostigmine, physostigmine readily penetrates the blood-brain barrier.
Physostigmine's activity is terminated via hydrolysis by cholinesterases. The ultimate fate and mode of excretion of physostigmine have not been fully elucidated, although it is known that only very small amounts of physostigmine are excreted in urine. In several healthy individuals, a terminal elimination half-life of 15-40 minutes has been reported.100, 101
Physostigmine salicylate is the salicylic acid derivative of an alkaloid extracted from dried ripe seeds of Physostigma venenosum Balfour (Fam. Leguminosae) (Calabar bean). The drug occurs as white, shiny crystals or white powder and has solubilities of approximately 13.3 mg/mL in water and 62.5 mg/mL in alcohol at 25°C. Physostigmine salicylate injection has a pH of 3.5-5.
Physostigmine and its salts acquire a red tint on contact with metals or after long exposure to heat, light, or air. This color change indicates hydrolysis to eseroline and oxidation to rubreserine. Further degradation produces eserine blue and eserine brown. The injection should not be used if it is more than slightly discolored. Although coloration of physostigmine solutions always indicates some loss of potency, lack of coloration of solutions of physostigmine salicylate does not necessarily assure full activity because eseroline, a colorless product of hydrolysis, possesses little or no activity.
Physostigmine salicylate solutions should not be sterilized by heat and should be stored in tight, light-resistant containers. Physostigmine salicylate injection should be stored at a controlled room temperature between 15-30°C. Commercially available physostigmine salicylate injection has an expiration date of 2 years following the date of manufacture.
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
---|---|---|---|---|
Bulk | Powder* | |||
Parenteral | Injection | 1 mg/mL* |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
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